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Research Overview

Gap Junction Background

The essential role of gap junctional intercellular communication in the normal functioning of cells and its relationship to disease is only beginning to be understood. Gap junction channels assemble when connexins oligomerize into a connexon or hemichannel and dock with a connexon from a neighboring cell. These channels cluster at defined cell-cell contacts to form gap junctions. It is now apparent that most human cells express more than one of the 21 members of the connexin family. Therefore, in addition to homomeric, homotypic and homocellular gap junctions, a diverse arrangement of heteromeric, heterotypic and heterocellular gap junctions exist between contacting cells. The complexity of channel constituents and arrangements within tissues is thought to be critical in selective passage of small biological molecules, like secondary messengers, from one cell to another. Interestingly, the generation of connexin null mice has revealed a number of defects ranging from embryonic lethal to relatively normal animals. These findings highlight the importance of connexins in nearly every major organ in the body. In the last couple of decades, mutations in the genes encoding several members of the connexin (Cx) family of gap junction proteins have been linked to a number of human diseases including a wide array of skin diseases and developmental disorders, all of which are currently under investigation in the Laird laboratory.

Pannexin Background

Upon their discovery,
pannexins (Panxs) gained instant attention from the gap junction community as
they were shown to share sequence homology to the invertebrate gap junction
proteins innexins. While the proposed
role of pannexins as molecular constituents of intercellular channels remains
controversial, there is general agreement that Panx1 forms large single
membrane channels at the cell surface that serve a role in paracrine signaling.
For example, Panx1 and Panx3-mediated ATP release plays a role in the
propagation of calcium waves possibly through an interaction with purinergic
receptors. ATP and UTP released via
Panx1 channels also act as "find-me" signals for apoptotic cell
clearance, regulate vascular tone and mucociliary lung clearance. Signaling
through Panx1 channels can also be detrimental and contribute to cell death and
seizures under ischemic or epileptic conditions, lead to inflammatory bowel
disease and promote melanoma disease progression. Panx3 has been reported to play a role in the
proliferation/differentiation of keratinocytes, chondrocytes and osteoblasts.

In recent years our laboratory cloned all three mouse pannexins,
developed an arsenal of well-characterized and reliable site-specific
antibodies and established an array of pannexin expression constructs. Through
the use of this molecular toolkit we discovered that members of the pannexin
family are long-lived, channel-forming glycoproteins that function at the cell
surface in ATP release. Other studies highlighted the regulatory role of Panx1
and Panx3 in keratinocyte differentiation and maintenance of the epidermis
while Panx3 was found to be important in osteoprogenitor cells, chondrocytes
and osteoblasts. Therefore to fully understand the role of pannexin channels in
skin and cartilage we will continue our biochemical and cell biological studies
on pannexin function and employ genetically modified mice to dissect the unique
and overlapping roles of Panx1 and Panx3 in
vivo.